DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

“A PROCESS FOR PREPARATION OF SUBSTITUTED BENZOIC ACIDS”

SRF LIMITED, AN INDIAN COMPANY,
SECTOR 45, BLOCK-C, UNICREST BUILDING,
GURGAON – 122003,
HARYANA (INDIA)

The following specification particular describe the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention provides a process for preparation of halogen substituted nitrobenzoic acid of formula I.

Formula I
wherein X is a halogen selected from Cl, F, Br and I, and n is a number selected from 1-3.

BACKGROUND OF THE INVENTION
The compounds of present invention are important intermediates in the pharmaceutical industry and find application as an intermediate in albaconazole, an antifungal and a neuroprotectant.
PCT Application No. 1987007602 provides a process for preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid by oxidising 2-chloro-4-fluorotoluene using potassium permanganate followed by nitration using nitric acid to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid.
PCT Application No. 2001083459 provides a process for preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid from 2-chloro-4-fluorobenzoic acid using 90% nitric acid in presence of concentrated sulfuric acid.
The processes cannot be used commercially due to low yield and multiple operations.
Chinese Patent No. 106905161 provides a process for preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid from 2-chloro-4-fluorobenzoic acid using concentrated sulfuric acid and fuming nitric acid in presence of cobalt chloride and zirconium chloride.
Chinese Application No. 112079703A provides a process for preparation of 2-chloro-4-fluoro-benzaldehyde comprising reacting 4-fluorobenzaldehyde with chloramine chlorination reagent in presence of an acid solution at 40-80?.
Chinese Application No. 107556289A gives a process for preparation of 2-chloro-4-fluorobenzoic acid from 2-chloro-4-fluorobenzaldehyde using aqueous sodium chlorite and hydrochloric acid in acetonitrile.
There is a need in the art to develop a simpler process for preparation of compound of formula I without using metal catalyst that does not require complex purification techniques.
The present invention provides a direct process for preparation of compound of formula I from a compound of formula IV without using any metal catalyst. The process not only obviate the complex purification operations but also provide good yields without compromising on product purity.

OBJECT OF THE INVENTION
The present invention provides an economical process for preparation of a compound of formula I.

Formula I
wherein X is a halogen selected from Cl, F, Br and I, and n is a number selected from 1-3.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for preparation of a compound of formula I, comprising the steps of:
i) chlorinating a compound of formula IV,

Formula IV
wherein X is as defined above,
with a chlorinating agent in a solvent to obtain a compound of formula III;

Formula III
wherein X is as defined above,
ii) oxidising the compound of formula III with an oxidising agent in a solvent to obtain a compound of formula II; and

Formula II
wherein X is as defined above,
iii) nitrating the compound of formula II using nitric acid to obtain the compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, the compound of formula I is selected from 2-chloro-4-fluoro-5-nitrobenzoic acid, 2-chloro-3-bromo-4-fluoro-5-nitrobenzoic acid and 2-chloro-6-bromo-4-fluoro-5-nitrobenzoic acid, or the like.
In an embodiment, the compound of formula II is selected from 2-chloro-4-fluorobenzoic acid, 2-chloro-3-bromo-4-fluorobenzoic acid and 2-chloro-6-bromo-4-fluorobenzoic acid, or the like.
In an embodiment, the compound of formula III is selected from 2-chloro-4-fluorobenzaldehyde, 2-chloro-3-bromo-4-fluorobenzaldehyde and 2-chloro-6-bromo-4-fluorobenzaldehyde or the like.
In an embodiment, the compound of formula IV is selected from 4-fluorobenzaldehyde, 3-bromo-4-fluorobenzaldehyde and 6-bromo-4-fluorobenzaldehyde or the like.
As used herein, solvent is selected from an organic solvent selected from a group consisting of dichloromethane, acetonitrile, acetone, dichloroethane, tetrahydrofuran, ethyl acetate, methyl acetate, tert-butyl methyl ether, diethyl ether, ethanol, and methanol or the like or acid solvent selected from a group consisting of an acetic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, chlorodifluoroacetic acid, trichloroacetic acid and conc. hydrochloric acid or a mixture thereof.
In an embodiment, a compound of formula IV is chlorinated using a chlorinating agent to obtain a compound of formula III.
As used herein, “chlorinating agent” is selected from a group consisting of N-chlorosuccinimide, N-chlorophthalimide, N-chlorosaccharin, 1,3-dichloro-5,5-dimethylhydantoin and chlorine, or the like.
The molar ratio of chlorinating agent to compound of formula IV is in the range of 1 to 1.5, preferably in the range of 1.1 to 1.3.
The chlorinating agent is added continuously or in the multiple lots in the chlorination reaction.
In an embodiment, the addition of chlorinating agent is in multiple lots. The number of lots depend on the reaction batch size and may vary from 2-8.
In another embodiment, the chlorinating agent is added continuously or a lot-wise in the reaction mass in the solution form, wherein chlorinating agent is dissolved in a solvent and charged in the reaction mass continuously.
In an embodiment, the step of chlorination of a compound of formula IV is carried out by dropwise addition of compound of formula IV into a solvent at temperature between 0-10?.
In an embodiment, the step of chlorination of a compound of formula IV is carried out using acidic solvent selected from a group consisting of acetic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, chlorodifluoroacetic acid and trichloroacetic acid, or a mixture thereof.
In an embodiment, the step of chlorination of a compound of formula IV is carried out by dropwise addition of compound of formula IV into the acidic medium at temperature between 0-10?.
In preferred embodiment, the step of chlorination is carried out in a mixture of trifluoroacetic acid and sulfuric acid.
In preferred embodiment, the step of chlorination is carried out using a mixture of trifluoroacetic acid (3-4 moles) and sulfuric acid (2-3 moles).
The chlorination of compound of formula IV is carried out a temperature in the range from 0-80?.
In an embodiment, the chlorination of 4-fluorobenzaldehyde is carried out using N-chlorosuccinimide to obtain 2-chloro-4-fluorobenzaldehyde in a mixture of trifluoracetic acid and sulfuric acid.
After chlorination, the reaction mass is quenched with water and extracted with an organic solvent.
In an embodiment, the compound of formula III is isolated and further oxidised with an oxidising agent to obtain a compound of formula II.
In another embodiment, the compound of formula IV is chlorinated using a chlorinating agent and is oxidised in-situ using an oxidising agent to form a compound of formula II.
In an embodiment, the present invention provides a process for preparation of a compound of formula I, comprising the steps of:
i) chlorinating a compound of formula IV with a chlorinating agent to obtain a reaction mass followed by treating with an oxidising agent to obtain a compound of formula II; and
ii) nitrating the compound of formula II using nitric acid to obtain the compound of formula I.
In an embodiment, after chlorination, the reaction mass was extracted with an organic solvent.
As used herein, the “oxidising agent” is selected from a group consisting of chlorinated oxidising agent such as sodium chlorite, potassium chlorite and sodium perchlorate, or the like. The oxidising agent may be used in solution form or in aqueous solution form.
The molar ratio of oxidising agent to compound of formula III is in the range of 1 to 5, preferably 1 to 3.
In preferred embodiment, the oxidation of compound of formula III is carried out using sodium chlorite. In another preferred embodiment, the 34% aqueous solution of sodium chlorite is used as oxidising agent.
The oxidation of compound of formula III is carried out in presence of organic solvent, preferably acetonitrile.
The oxidation is carried out at a temperature selected in the range from 0-90?.
After oxidation, the reaction is acidified to pH 1-3 using an acid, such as hydrochloric acid, quenched with water and extracted with an organic solvent.
In another embodiment, 2-chloro-4-fluoro-5-benzaldehyde is oxidised using 34% aqueous sodium chlorite to obtain 2-chloro-4-fluoro-5-benzoic acid in acetonitrile.
In an embodiment, 4-fluorobenzaldehyde is chlorinated using n-chlorosuccinimide to obtain reaction mass, which further oxidised using sodium chlorite to obtain 2-chloro-4-fluorobenzoic acid in acetonitrile.
In an embodiment, the compound of formula II is nitrated to obtain a compound of formula I in presence of acid solvent.
As used herein, “nitrating agent” may be selected from a group consisting of nitric acid and nitrates such as potassium nitrate and sodium nitrate, or the like.
In an embodiment, nitrating agent is used as such or with an acid and acid may be selected from glacial acetic acid, trichloroacetic acid, trifluoroacetic acid and phosphoric acid or sulfuric acid.
In preferred embodiment, the nitrating agent is a mixture of concentrated nitric acid and concentrated sulfuric acid.
The nitration is carried out a temperature selected in the range from 0-60?.
The molar ratio of nitrating agent to compound of formula III or compound of formula II is in the range of 1 to 5, preferably 3 to 4.5.
After nitration, the reaction mass is quenched with water and extracted with an organic solvent.
In an embodiment, the nitration of 2-chloro-4-fluorobenzoic acid is carried out using a mixture of concentrated nitric acid and concentrated sulfuric acid to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid.
The purification technique used for purification of compound of formula I to IV may be selected from distillation, boil-off, solvent extraction, solvent washing, thin layer chromatography and filtration, or the like.
In an embodiment, the present invention provides a process for preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid, comprising the steps of:
i) chlorinating 4-fluorobenzaldehyde with N-chlorosuccinimide in a mixture of trifluoroacetic acid and sulfuric acid to obtain 2-chloro-4-fluorobenzaldehyde;
ii) oxidising 2-chloro-4-fluorobenzaldehyde with 34% sodium chlorite in acetonitrile to obtain 2-chloro-4-fluorobenzoic acid;
iii) nitrating 2-chloro-4-fluorobenzoic acid with a mixture of fuming nitric acid and sulfuric acid to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid.
In an embodiment, the present invention provides a process for preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid, comprising the steps of:
i) chlorinating 4-fluorobenzaldehyde with N-chlorosuccinimide in trifluoroacetic acid and sulfuric acid to obtain a reaction mass, oxidising the reaction mass with 34% sodium chlorite to obtain 2-chloro-4-fluorobenzoic acid;
ii) nitrating 2-chloro-4-fluorobenzoic acid with fuming nitric acid to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid.
In an embodiment, a process for preparation of 2-chloro-4-fluorobenzaldehyde by reacting 4-fluorobenzaldehyde with N-chlorosuccinimide in a mixture of trifluoroacetic acid and sulfuric acid at 70?.
In an embodiment, a process for preparation of 2-chloro-4-fluorobenzoic acid by oxidising 2-chloro-4-fluorobenzaldehyde with 34% sodium chlorite in acetonitrile.
In an embodiment, a process for preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid by reacting 2-chloro-4-fluorobenzoic acid with a mixture of nitric acid and sulfuric acid.
In an embodiment, the present invention provides the compound of formula I, having purity greater than 99% and yield greater than 70%.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLES
Example 1: Preparation of 2-chloro-4-fluorobenzaldehyde
Trifluoroacetic acid (354 g, 3.10 moles) and sulfuric acid (214 g, 2.18 moles) were charged into a reactor. The agitation was started, and acid mixture was cooled to 0?. 4-Fluorobenzaldehyde (35 g, 0.28 moles) was added dropwise into acid mixture between 0 and 5 ?. After complete addition, the reaction mass temperature was adjusted to 70?. N-chlorosuccinimide (48.60 g, 0.36 moles) was charged into the reaction mass in three lots and after addition of every lot, reaction mass was stirred for 4 hours at 70?. The sample was analysed on gas chromatography. After reaction completion, the reaction mass was cooled to 30? and water (2800 g, 155 moles) was added to quench the reaction mass. Then, dichloromethane (420 g, 4.94 moles) was charged in the reaction mass and stirred for 30 minutes. The layers were separated from the reaction mass. The organic layer was washed with 35 mL of saturated sodium bicarbonate solution. The organic layer was taken for distillation and isolate the product (Purity: 99.1%, Yield : 80%).
Example 2: Preparation of 2-chloro-4-fluorobenzoic acid
Acetonitrile (700 ml) was charged in a reactor and cooled to 0?. 2-chloro-4-fluorobenzaldehyde (35 g, 0.22 moles) was added in the acetonitrile and agitated the mass until dissolved. 34% of aqueous NaClO2 solution (176.2 g, 0.66 moles) was added into the reaction mass with well agitation. Then, 27% HCl solution (118 g, 0.87 moles) was added dropwise at 0 and 5?. After completion of the addition, the reaction mass was stirred for additional 0.5 hour. The reaction mass temperature was increased to 80? and stirred for additional 0.5 hour. The reaction mass was diluted with water (350 mL) and pH was adjusted to 2 by using 6 N HCl. Then product was extracted using dichloromethane (350 g, 4.12 moles). Organic layer was evaporated and purified to get desired 2-chloro-4-fluorobenzoic acid (Purity: 99.19%, Yield: 80%) in pure form.
Example 3: Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid
Sulfuric acid (218g, 2.20moles) and 2-chloro-4-fluorobenzoic acid (23g, 0.13moles) were added into the reactor. Cooled the above reaction mixture to 0?. A mixture of concentrated nitric acid (12.3 g, 0.19moles) and concentrated sulfuric acid (43.6g, 0.44moles) was added into the reaction mass as dropwise between 0-5?. The reaction mass was maintained at 0? for additional one hour. Then, heated to 50? and agitated for additional 3 hours. Progress of reaction is monitored by HPLC. After getting the desired conversion, the reaction mass was cooled to 25? and poured into ice water. The resultant mass was filtered to obtain white solid. The white solid was washed with water, dried at 60? for 8-10 h to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid (Purity: 99.3%, Yield: 80%).
Example 4: Preparation of 2-chloro-4-fluorobenzoic acid (chlorination and oxidation in-situ)
Trifluoroacetic acid (354 g, 3.10 moles) and sulfuric acid (214 g, 2.18 moles) were charged into a reactor. The agitation was started, and acid mixture was cooled to 0?. 4-Fluorobenzaldehyde (35 g, 0.28 moles) was added dropwise into acid mixture between 0 and 5 ?. After complete addition, the reaction mass temperature was adjusted to 70?. N-chlorosuccinimide (48.60 g, 0.36 moles) was charged into the reaction mass in three lots and after addition of every lot, reaction mass was stirred for 4 hours at 70?. The reaction mass was cooled to 30?. Charged water, stir for 30 minutes, and separate the layers. Organic layer was cooled to 0? and add acetonitrile (420 g, 10.23 moles) followed by addition of 34% of aqueous NaClO2 solution (176.2 g, 0.66 moles) into it while agitation. Then, 27% HCl solution (118 g, 0.87 moles) was added dropwise at 0 and 5?. After completion of addition, the reaction mass was stirred for additional 0.5 hour. The reaction mass temperature was increased to 80? and stirred for additional 0.5 hour. The reaction mass was diluted with water (350 mL) and pH was adjusted to 2 by using 6 N HCl. Then product was extracted using dichloromethane (350 g, 4.12 moles). Organic layer was evaporated and purified to get desired 2-chloro-4-fluorobenzoic acid (Purity: 99.01, Yield: 82%) in pure form.

,CLAIMS:

WE CLAIM
1. A process for preparation of a compound of formula I, comprising the steps of:

Formula I
wherein X is a halogen selected from Cl, F, Br and I, and n is a number selected from 1-3.

i) chlorinating a compound of formula IV,

Formula IV
wherein X is as defined above,
with a chlorinating agent in a solvent to obtain a compound of formula III;

Formula III
wherein X is as defined above,
ii) oxidising the compound of formula III with an oxidising agent in a solvent to obtain a compound of formula II; and

Formula II
wherein X is as defined above,
iii) nitrating the compound of formula II using nitric acid to obtain the compound of formula I.
2. The process as claimed in claim 1, wherein the chlorinating agent is selected from a group consisting of N-chlorosuccinimide, N-chlorophthalimide, N-chlorosaccharin, 1,3-dichloro-5,5-dimethylhydantoin and chlorine.
3. The process as claimed in claim 1, wherein the chlorination of the compound of formula IV is carried out at a temperature selected in the range from 0-80?.
4. The process as claimed in claim 1, wherein the oxidising agent is a chlorinated oxidising agent selected from the group consisting of sodium chlorite, potassium chlorite and sodium perchlorate.
5. The process as claimed in claim 1, wherein the molar ratio of oxidising agent to compound of formula III is in the range of 1 to 5.
6. The process as claimed in claim 1, wherein the oxidation is carried out at a temperature selected in the range from 0-90?.
7. The process as claimed in claim 1, wherein the nitration is carried out at a temperature selected in the range from 0-60?.
8. The process as claimed in claim 1, wherein the molar ratio of nitrating agent to compound of formula III or compound of formula II is in the range of 1 to 5.
9. The process as claimed in claim 1, wherein, the compound of formula IV is chlorinated using a chlorinating agent and is oxidised in-situ using an oxidising agent to form a compound of formula II.
10. The process as claimed in claim 1, wherein the solvent is an organic solvent selected from a group consisting of dichloromethane, acetonitrile, acetone, dichloroethane, tetrahydrofuran, ethyl acetate, methyl acetate, tert-butyl methyl ether, diethyl ether, ethanol and methanol or an acidic solvent selected from a group consisting of acetic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, chlorodifluoroacetic acid and trichloroacetic acid.

Dated on 20th day of December 2022.